This project covers a broad range of studies which focus on elucidating risk factors for, and the natural history of, esophageal adenocarcinoma (esophageal cancer) and the precursor lesion Barretts esophagus (aka Barrett esophagus). Barretts esophagus is a metaplastic change in the lower esophagus which is characterized by the replacement of the native squamous cell epithelium with a glandular-type of epithelium. This metaplastic change is thought to be primarily the result of genotoxic damage induced by gastroesophageal refluxacid and bile salts reflux up into the esophagus, exposing cells not equipped to deal with these reactive chemicals. Re-epithelization with the metaplastic Barretts epithelium provides for a tissue which is better able to withstand the exposure to such compounds. However, it also increases the risk of esophageal adenocarcinoma approximately 10-50 fold that of the general population. The incidence of esophageal adenocarcinoma has increased over 650% in the United States over the last 35 years and most individuals present with late stage malignancies, resulting in a 5-year survival rate of less than 20%. This indicates that researchers need to be able to better identify those at high risk and Barretts esophagus is a good starting point. However, although this metaplasia greatly increases the risk of esophageal adenocarcinoma relative to the general population, the absolute risk remains low at around 0.5% or 1 in 200 patient years of follow-up. This is because approximately 90% of individuals who develop esophageal adenocarcinoma are diagnosed at their first (index) endoscopy. Thus, not only do we need to be able to better identify those with high risk (Barretts esophagus) in the general population, we also need to be able to triage these individuals into high and low risk groups so that surveillance resources can be focused on those who most need them, which would make the cost-benefit equation of surveillance endoscopy more attractive. Therefore, the ultimate goals of all the studies within this project seek to better understand the natural history of this disease, risk factors for progression, diagnostic markers and modalities with high sensitivity, and prognostic biomarkers for efficient triaging of risk.The Barrett's Breath Test Pilot (CAS ID:10592) is assessing the utility of quantifying volatile organic compounds (VOCs) in the breath for a future epidemiologic study. Specially, it is assessing what the intraclass correlation coefficients are for VOCs over a 98 day period, with three time points with biological duplicates taken from each of five volunteers. The Barrett's Esophagus Consortium project (CAS ID:10593) is a pooling project that brings together and harmonizes data from five case-control studies of Barrett's esophagus. We have already assessed the exposures tobacco smoking (published in Gastroenterology), body mass index and waist circumference (published in Gut), alcohol (published in American Journal of Gastroenterology). We are currently working on analyses of GERD and NSAID use; adiponectin; and insulin-like growth factors (IGFs) in relation to this precursor metaplasia for publication. The Esophageal Cancer in SEER-Medicare project (CAS ID:10633) is assessing metabolic syndrome in relation to Barrett's esophagus (published in Journal of Clinical gastroenterology) and esophageal adenocarcinoma (manuscript in progress), as well as the comparative utility of staging modalities in relation to survival following diagnosis of esophageal adenocarcinoma (In Press). We are also assessing whether there is heterogeneity in the natural history of esophageal adenocarcinoma.The CPRD EAC Progression Study is an analysis in collaboration with our colleagues at Boston University and will enable us to assess whether metabolic syndrome is a risk factor for progression from Barretts esophagus to esophageal adenocarcinoma. This analysis is based in the Clinical Practice Research Datalink (CPRD) which was formerly called the General Practice Research Database (GPRD). The manuscript is currently being drafted. In the Hormones in Barrett's Esophagus project (CAS ID:10638) we have assessed circulating androgens and estrogens in Barrett's esophagus patients compared with gastroeosphageal reflux disease controls in the BEEDS study based at the Walter Reed (In press). We are currently assessing similar exposures in a second population for external replication as well as expansion to esophageal cancer (adenocarcinoma).The Kaiser BE Cohort project will enable us to assess different risk factors for progression from Barretts esophagus to esophageal adenocarcinoma. Currently, a majority of evidence for Barretts esophagus patients comes from studies of risk factors for esophageal adenocarcinoma but a majority of such patients are never previously diagnosed with Barretts esophagus. Thus a disconnect may exist in the population for study and the population under surveillance. These analyses will provide evidence that is directly applicable for a Barretts esophagus population undergoing surveillance. All of these projects are closely aligned to the aims of elucidating the etiology of Barrett's esophagus and esophageal adenocarcinoma as well as providing potential utility for diagnostics and prognostics.